Our long-term goal is to develop an effective immunologic therapy to improve the survival of patients with ovarian and primary peritoneal cancer. Despite the advent of newer chemotherapies, the 5-year survival for patients with advanced disease remains 25%. The development of immune and biologic therapies is necessary to complement traditional cytotoxic treatments. In this application, we propose to test the CENTRAL HYPOTHESIS that cellular immunity may be augmented by adoptive immunotherapy using autologous T cells lentivirally transduced with anti-mesothelin chimeric immunoreceptor (CIR) scFv in patients with intraperitoneal malignancies through the following three SPECIFIC AIMS: (1) To conduct a phase I clinical trial to study the safety and feasibility of anti-mesothelin CIR transduced autologous T cells in patients with chemotherapy-refractory advanced ovarian, primary peritoneal, and pancreatic cancer, as well as peritoneal mesothelioma, We plan to administer a single dose of transduced autologous T cells either intravenously or intraperitoneally to patients who have measurable disease following at least two prior courses of cytotoxic chemotherapy. We will determine the safety and feasibility of treatment by determining (a) clinical toxicity, (b) the response rate through 6 months post- treatment, (c) the engraftment and persistence of transduced T cells in the peripheral circulation, (d) the development of host immunity to transduced T cells, (e) and the safety of lentiviral engineered cell products by monitoring for the presence of VSV-G RNA, VSV-G antibody responses, and biological RCL testing. (2) To determine the induction or enhancement of anti-tumor immunity for patients undergoing treatment, and to examine T cell trafficking by performing ELISPOT assays, and post-treatment tumor biopsies for tumor- infiltrating lymphocytes and down-regulation of mesothelin expression. (3) To examine factors effecting the development of host immunity by determining the level of soluble mesothelin in patient serum by ELISA, the level of regulatory T cells by flow cytometry, and the presence and levels of serum Th1 cytokines by ELISA. Project Relevance: Ovarian cancer is the leading cause of gynecologic cancer death, and though most patients respond to initial chemotherapy, the majority eventually relapse and die of chemotherapy resistant disease. We aim to develop complimentary immunotherapies to augment traditional treatment strategies. [unreadable] [unreadable] [unreadable]